Abstract: Currently there is no effective treatment for Scleroderma (systemic sclerosis), an autoimmune disease unresponsive to immunosuppressive therapy. This proposal is based upon the belief that two main barriers exist towards the cure of this disease. First, there is no published technology for isolating unmanipulated pathogenic T cells from patients with autoimmunity. Second, current immunosuppressive medications do not target the correct immune cells in these patients. In order to improve the treatment and survival of these patients it is critical to: identify the role that the immune system plays in this disease, determine the effect that current immunosuppressive therapies have on the patients' autoreactive immune response, identify new therapeutic targets by fully characterizing the autoreactive immune response in scleroderma, and finally to design novel inhibitors to these targets. Our specific hypothesis is that unmanipulated self- reactive T cell clones isolated directly from patients with scleroderma can be used to identify novel therapeutic targets and small molecules capable of selectively binding these pathogenic cells. This hypothesis is based upon the following observations. 1) We have developed a technique to directly isolate pure populations of clonally expanded T cells from patients with autoimmunity. 2) A high affinity ligand for a subpopulation of activated T cells was identified through a combinatorial screening approach. 3) Screening combinatorial libraries has identified inhibitors of key intracellular pathway required for T cell activation. Based upon these observations the experimental focus of this proposal will be to combinatorial libraries to identify novel T cell-inhibiting small molecules and T cell-specific ligands in an attempt to develop a highly effective therapeutic that can target and destroy pathogenic T cells in the setting of scleroderma and other immune mediated diseases of the skin.